Background-Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown.Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. Methods and Results-To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS Ϫ/Ϫ mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS Ϫ/Ϫ mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. Conclusions-These

Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.

Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endothelial NO synthase (eNOS) null mice. Extrapolation of these findings to humans is difficult, however, because eNOS gene deficiency has not been reported. eNOS gene polymorphism and impaired NO synthesis, however, have been reported in several cardiovascular disease states and could predispose to insulin resistance. High-fat diet induces insulin resistance and arterial hypertension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pressure in eNOS(+/-) mice. When fed a normal diet, these mice had normal insulin sensitivity and were normotensive. When fed a high-fat diet, however, eNOS(+/-) mice developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulin-stimulated glucose utilization than control mice. The partial deletion of the eNOS gene does not alter insulin sensitivity or blood pressure in mice. When challenged with nutritional stress, however, partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension, providing further evidence for the importance of this gene in linking metabolic and cardiovascular disease.

Background and Purpose-Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir Ϸ7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. Methods-We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. Key Words: acute ischemic stroke Ⅲ functional outcome Ⅲ J-shaped association Ⅲ poststroke hyperglycemia Ⅲ serum glucose H yperglycemia is commonly encountered in patients with acute ischemic stroke, with estimates varying and depending on the frequency of glucose measurements and the criteria used to define hyperglycemia. 1 The incidence of poststroke hyperglycemia is estimated at 45% in studies with frequent glucose measurements and a threshold value of 7 mmol/L to define hyperglycemia. 2 Because the prevalence of previously diagnosed diabetes mellitus in stroke patients is estimated between 10% and 20%, diabetes mellitus is obviously not the only underlying pathophysiologic mechanism of poststroke hyperglycemia. 3 Previously undiagnosed diabetes mellitus and impaired glucose tolerance account for a further 5% to 28%. 3 In addition, 10% to 20% of stroke patients present with hyperglycemia with normal glycosylated hemoglobin. 4 This is considered as a neurohumoral stress response, although studies on the association between serum cortisol and poststroke hyperglycemia yielded conflicting results. 4 Hyperglycemia after stroke is independently associated with infarct volume in magnetic resonance and spectroscopy studies, 5 and poor functional outcome. 6 However, the UK Glucose Insulin in Stroke Trial (GIST-UK) showed no clinical benefit of treating hyperglycemia rapidly with glucose-potassium-insulin infusion. 7 Moreover, mortality was higher in those patients with greatest glucose reductions (Ͼ2 mmol/L), implying a possibly deleterious effect when glucose levels decrease to less than a critical threshold. 7 An animal model study demonstrated that the association between serum glucose and cerebral infarct volume is described by a U-shaped curve with a nadir of approximately 7 mmol/L. 8 However, a similar curve in human studies was never reported.Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.